Infection of cells by human immunodeficiency virus (HIV) is mediated by binding to CD4 expressed on the surface of the cell and fusion with the cellular membrane. Fusion does not occur in most nonhuman cells even when they express human CD4, indicating that one or more human accessory factors also mediate virus infection. Recently, a seven-transmembrane domain protein was shown to serve as an accessory factor for T-cell-tropic (T-tropic) HIV-1 isolates. See, Feng et al., Science 272:872-877, 1996, and Berson et al. (1996) J Virol 70 (9): 6288-95. Expression of this glycoprotein, termed fusin, in murine, feline, simian and quail cell lines, in conjunction with human CD4, rendered these cells permissive for HIV-1 envelope glycoprotein (Env)-mediated infection. Expression of CD4 or fusin alone did not permit infection. In addition, introduction of fusin and CD4 into a human cell line, U87MG, which is resistant to HIV-1 induced syncytium formation and to infection by HIV-1 when expressing CD4 alone made the cell line permissive for HIV Env-mediated cell--cell fusion. Fusion was observed with T-tropic Env proteins. Macrophage-tropic (M-tropic) Env proteins from the SF162, ADA, and Ba-L HIV-1 strains did not fuse with cells expressing fusin and CD4.
A second member of the seven-transmembrane domain protein family, the beta-chemokine receptor CKR-5 (alternately known as "CC-CKR5" or as "CCR-5"), mediates infection of macrophage by M-tropic HIV viruses. Co-expression of CKR-5 with CD4 enables nonpermissive cells to form syncytia with cells expressing M-tropic, but not T-tropic, HIV-1 env proteins. Expression of CKR-5 and CD4 permits entry of M-tropic, but not T-tropic, virus strain. See, Doranz et al. (1996) Cell 85 (7): 1149-58; Feng et al. (1996) Science 272 (5263): 872-7; Alkhatib et al. (1996) Science 272 (5270): 1955-8, and Deng et al. (1996) Nature 381 (6584): 661-6. Some T cells also express CKR-5 (e.g., in addition to fusin), and CKR-5 can also mediate infection of M-tropic HIV viruses into these T cells.
A dual-tropic primary HIV-1 isolate (89.6) utilizes both Fusin and CKR-5 as entry cofactors. See, Doranz et al., id. Cells expressing the 89.6 env protein form syncytia with QT6 cells expressing CD4 and either Fusin or CKR-5. The beta-chemokine receptors CKR-3 and CKR-2b support HIV-1 89.6 env-mediated syncytia formation but do not support fusion by any of the T-tropic or M-tropic strains tested. This indicates that the T-tropic viruses characteristic of disease progression may evolve from purely M-tropic viruses prevalent early in virus infection through changes in the env protein that enable the virus to use multiple entry cofactors.